US20170304274A1 - Dyslipidemia therapeutic agent - Google Patents

Dyslipidemia therapeutic agent Download PDF

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Publication number
US20170304274A1
US20170304274A1 US15/513,609 US201515513609A US2017304274A1 US 20170304274 A1 US20170304274 A1 US 20170304274A1 US 201515513609 A US201515513609 A US 201515513609A US 2017304274 A1 US2017304274 A1 US 2017304274A1
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Prior art keywords
salt
solvate
niacin
ldl
nicotinic acid
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US15/513,609
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English (en)
Inventor
Yuta Inokuchi
Toshiaki Takizawa
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Kowa Co Ltd
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Kowa Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a composition containing (R)-2-[3-[[N-(benzoxazol-2-yl) -N-3-(4-methoxyphenoxy) propyl]aminomethyl]phenoxy] butyric acid, and nicotinic acid, nicotinic acid amide, which are collectively referred to as niacin, an ester derivative thereof, or the like, and combination use thereof for preventing and/or treating dyslipidemic conditions such as atherosclerosis or hypercholesterolemia.
  • Dyslipidemia particularly hypercholesterolemia has become a disease having a quite high degree of medical satisfaction due to advent of statins.
  • statins the lower, the better.
  • More strict lipid control has been recommended.
  • Many patients cannot reach the intended LDL-C level in blood only with statins. Combination use of multiple pharmaceutical agents has been also required (Non-Patent Document 1).
  • PPAR is one of receptors belonging to a nuclear receptor family. Existence of three subtypes ( ⁇ , ⁇ , and ⁇ ) is known for this receptor (Non-Patent Document 2). Among these types, PPAR ⁇ is mainly expressed in the liver. When PPAR ⁇ is activated, production of apo C-III is suppressed, followed by activation of lipoprotein lipase (LPL). As a result, fat is decomposed.
  • LPL lipoprotein lipase
  • PPAR ⁇ agonist for example, unsaturated fatty acids and fibrate pharmaceutical agents such as fenofibrate, bezafibrate, or gemfibrozil have been known (Non-Patent Document 3). In recent years, a compound having a stronger and more selective PPAR ⁇ activating effect than a conventional fibrate pharmaceutical agent has been reported (Patent Document 1).
  • Niacin is a water-soluble vitamin belonging to a vitamin B complex and is constituted by nicotinic acid and nicotinic acid amide, and is biosynthesized also in a human body. Niacin is widely present in plants and animals, and is usually ingested through food. Each of Niacin and niacin ester derivatives (niceritrol) acts as a coenzyme (nicotinamide adenine dinucleotide (NAD)) of an oxidation-reduction enzyme in energy metabolism, and has been used for treating carbohydrate-lipid metabolism for many decades (Non-Patent Documents 4 and 5).
  • Non-Patent Document 6 In a study using positive lipemia rats or fructose load hyperlipidemia rats, it has been reported that combination use of clofibrate and nicotinic acid brings about synergistic lowering of triglyceride in blood as compared with administration of each thereof (Non-Patent Document 7).
  • Non-Patent Document 8 Non-Patent Document 8
  • Patent Document 1 WO 2005/023777 A1
  • Patent Document 2 WO 2005/023777 A1
  • Non-Patent Document 1 Journal of Pharmacological Sciences 129, 267-270 (2007)
  • Non-Patent Document 2 J. Lipid Research, 37, 907-925 (1996)
  • Non-Patent Document 3 Trends in Endocrinology and Metabolism, 15 (7), 324-330 (2004)
  • Non-Patent Document 4 British Journal of Pharmacology, 153, S68-S75 (2008)
  • Non-Patent Document 5 Metabolism, 46 (4), 355-358 (1997)
  • Non-Patent Document 6 J Pharm Sci, 89 (8), 1046-53 (2000)
  • Non-Patent Document 7 Biochemical Pharmacology, 28, 1163-1167 (1979)
  • Non-Patent Document 8 Atherosclerosis, 37, 129-138 (1980)
  • An object of the present invention is to provide a pharmaceutical composition comprising a combination of pharmaceutical agents and combination use of pharmaceutical agents for preventing and/or treating dyslipidemic conditions such as atherosclerosis, hypercholesterolemia, or hyper LDL cholesterolemia.
  • the present invention provides a pharmaceutical composition for preventing and/or treating dyslipidemia, comprising a) (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy) propyl]aminomethyl]phenoxy] butyric acid, a salt thereof, or a solvate thereof, and b) niacin, an ester derivative thereof, a salt thereof, or a solvate thereof.
  • the present invention provides a pharmaceutical composition for preventing and/or treating hyper LDL cholesterolemia, containing a) (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy) propyl]aminomethyl]phenoxy] butyric acid, a salt thereof, or a solvate thereof, and b) niacin, an ester derivative thereof, a salt thereof, or a solvate thereof.
  • a pharmaceutical composition for preventing and/or treating dyslipidemia comprising (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy) propyl]aminomethyl]phenoxy] butyric acid (compound A), a salt thereof, or a solvate of either, and niacin, an ester derivative thereof, a salt of either, or a solvate of any of these.
  • a pharmaceutical composition for lowering LDL cholesterol comprising compound A, a salt thereof, or a solvate of either, and niacin, an ester derivative thereof, salt of either, or a solvate of any of these.
  • LDL-C LDL cholesterol
  • LDL-C hyper LDL cholesterolemia
  • a medicine for lowering LDL cholesterol obtained by combining a pharmaceutical composition comprising compound A, a salt thereof, or a solvate of either, and a pharmaceutically acceptable carrier; and a pharmaceutical composition comprising niacin, an ester derivative: thereof, a salt of either, or a solvate of any of these, and a pharmaceutically acceptable carrier.
  • LDL-C LDL cholesterol
  • LDL-C hyper LDL cholesterolemia
  • a method for preventing and/or treating dyslipidemia of a patient comprising: administering an effective amount of a pharmaceutical composition comprising compound A, a salt thereof, or a solvate of either, and niacin, an ester derivative thereof, a salt of either, or a solvate of any of these to a patient of dyslipidemia or a patient having a risk of suffering from dyslipidemia.
  • a method for lowering LDL cholesterol (LDL-C) of a patient comprising: administering an effective amount of a pharmaceutical composition comprising compound: A, a salt thereof, or a solvate of either, and niacin, an ester derivative thereof, a salt of either, or a solvate of any of these, to a patient requiring lowering of LDL cholesterol (LDL-C).
  • LDL-C LDL cholesterol
  • LDL-C LDL cholesterol
  • a pharmaceutical composition for preventing and/or treating dyslipidemia comprising, as an active ingredient, compound A, a salt thereof, or a solvate of either, which is used in combination with niacin, an ester derivative thereof, a salt of either, or a solvate of any of these.
  • a pharmaceutical composition for lowering LDL cholesterol comprising, as an active ingredient, compound A, a salt thereof, or a solvate of either, thereof, which is used in combination with niacin, an ester derivative thereof, a salt of either, or a solvate of any of these.
  • LDL-C LDL cholesterol
  • a pharmaceutical composition for preventing and/or treating dyslipidemia comprising, as an active ingredient, niacin, an ester derivative thereof, a salt of either or a solvate of any of these, which is used in combination with a pharmaceutical composition comprising compound A, a salt thereof, or a solvate of either, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for lowering LDL cholesterol comprising, as an active ingredient, niacin, an ester derivative thereof, a salt of either, or a solvate of any of these, which is used in combination with a pharmaceutical composition comprising compound A, a salt thereof, or a solvate of either, and a pharmaceutically acceptable carrier.
  • niacin, an ester derivative thereof, a salt, of either, or a solvate of any of these for manufacturing a pharmaceutical composition for preventing and/or treating dyslipidemia by combination use thereof with compound A, a salt thereof, or a solvate of either.
  • LDL-C LDL cholesterol
  • the pharmaceutical composition and the medicine according to the present invention exhibit an excellent effect of lowering LDL cholesterol in blood, and are useful for preventing and/or treating dyslipidemia, particularly hyper LDL cholesterolemia.
  • FIG. 1 illustrates LDL-C in plasma at the time of use of compound A (0.1 mg/kg) alone, use of nicotinic acid (100 mg/kg) alone, and combination use of compound A (0.1 mg/kg) and nicotinic acid (100 mg/kg).
  • compound A used in the present invention can be produced In accordance with a method described In WO 2005/023777 A1.
  • compound A can be produced in accordance with a method described in literature.
  • a chemical structural formula of compound. A is as follows.
  • the present invention can use a salt of compound A or a solvate thereof.
  • the salt and the solvate can be manufactured by a usual method.
  • the salt of compound A is not particularly limited as long as being pharmaceutically acceptable.
  • examples thereof include an alkali metal salt such as a sodium salt or a potassium salt; an alkaline earth metal salt such as a calcium salt, or a magnesium salt; an organic base salt such as an ammonium salt or a trialkylamine salt; a mineral acid salt such as a hydrochloride or a sulfate; and an organic acid salt such as an acetate.
  • solvate of compound A or a salt thereof examples include a hydrate and an alcohol solvate (for example, ethanol solvate).
  • Niacin is a compound also referred to as pyridine-3-carboxylic acid (nicotinic acid), pyridine-3-carboxylic acid amide (nicotinic acid amide), or vitamin B 3 .
  • niacin in the present invention include nicotinic acid and nicotinic acid amide.
  • Examples of an ester derivative of niacin include niceritrol. These compounds are also included in a concept of the present invention.
  • the salt of niacin or an ester derivative of niacin is not particularly limited as long as being pharmaceutically acceptable.
  • examples thereof include an alkali metal salt such as a sodium salt or a potassium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt; an organic base salt such as an ammonium salt or a trialkylamine salt; a mineral acid salt such as a hydrochloride or a sulfate; and an organic acid salt such as an acetate.
  • solvate of compound A or a salt thereof examples include a hydrate and an alcohol solvate (for example, ethanol solvate).
  • the pharmaceutical agents of the present invention are useful for preventing and/or treating dyslipidemia such as hypercholesterolemia or hyper LDL cholesterolemia.
  • dyslipidemia means a case where any one of a total triglyceride (TG) level, a total cholesterol (TC) level, a VLDL cholesterol (VLDL-C) level, a LDL cholesterol (LDL-C) level, and a HDL cholesterol (HDL-C) level in blood, or two or more thereof deviate from a range of normal values.
  • TG total triglyceride
  • TC total cholesterol
  • VLDL-C VLDL cholesterol
  • LDL-C LDL cholesterol
  • HDL-C HDL cholesterol
  • a disease requiring lowering of LDL cholesterol (LDL-C) in the present invention means a case where the LDL-C level in blood is higher than a normal value.
  • the pharmaceutical composition of the present invention can be formed into a dosage form such as a tablet, a capsule, a granule, a powder, a lotion, an ointment, an injection, or a suppository singly or using another pharmaceutically acceptable carrier.
  • a dosage form such as a tablet, a capsule, a granule, a powder, a lotion, an ointment, an injection, or a suppository singly or using another pharmaceutically acceptable carrier.
  • These formulations can be manufactured by a known method.
  • the formulation when a formulation for oral administration is manufactured, can be manufactured by appropriately combining and formulating a dissolving agent, such as gum tragacanth, gum arabic, a sucrose fatty acid ester, lecithin, olive oil, soybean oil, or PEG400; an excipient such as starch, mannitol, or lactose; a binder such as methyl cellulose, sodium carboxymethylcellulose, or hydroxypropylcellulose; a disintegrating agent such as crystalline cellulose or calcium carboxymethylcellulose; a lubricant such as talc or magnesium stearate; and a flow improver such as light anhydrous silicic acid.
  • a dissolving agent such as gum tragacanth, gum arabic, a sucrose fatty acid ester, lecithin, olive oil, soybean oil, or PEG400
  • an excipient such as starch, mannitol, or lactose
  • a binder such as methyl cellulose, sodium carboxymethylcellulose,
  • the pharmaceutical composition of the present invention it is possible to use a form in which an effect for preventing and/or treating dyslipidemia such as hypercholesterolemia or hyper LDL cholesterolemia is obtained by combining a) compound A, a salt thereof, or a solvate of either, and b) nicotinic acid and nicotinic acid amide collectively referred to as niacin, an ester derivative thereof, a salt of either, or a solvate of any of these, and by using a synergistic effect for raising HDL-C in blood due to administration of the two pharmaceutical agents in addition to an effect by each of the pharmaceutical agents.
  • the use form of the present invention is not limited thereto.
  • Compound A, a salt thereof, or a solvate of either, and nicotinic acid , nicotinic acid amide, which are collectively referred to as niacin, an ester derivative thereof, a salt of either, or a solvate of any of these may be administered simultaneously, or may be administered separately at an interval.
  • Compound A, a salt thereof, or a solvate of either, and nicotinic acid, nicotinic acid amide, which are collectively referred to as niacin, an ester derivative thereof, a salt of either, or a solvate of any of these may be formulated into a single formulation, or the two pharmaceutical agents may be formulated separately to be used as a kit. That is, the pharmaceutical composition of the present invention may be a kit formed by combining a pharmaceutical agent comprising at least one selected from compound A, a salt thereof, and a solvate of either as an active ingredient, and/or a pharmaceutical agent comprising at least one of the solvates.
  • a blending ratio between compound A, a salt thereof, or a solvate of either, and nicotinic acid, nicotinic acid amide, which are collectively referred to as niacin, an ester derivative thereof, a salt of either, or a solvate of any of these can be appropriately selected in a range of an effective dose of each active ingredient, but in general, is preferably from 1:1 to 1:10000, more preferably from 1:5 to 1:4000, and particularly preferably from 1:10 to 1:2000 in terms of a mass ratio as nicotinic acid.
  • dosage forms of the two pharmaceutical agents may be the same as or different from each other.
  • the numbers of dose for ingredients may be different from one another.
  • Compound A, a salt thereof, or a solvate of either of the present invention is administered orally or parenterally.
  • the dose of the pharmaceutical agents of the present invention vary according to a patient's weight, age, sex, symptoms, and the like. However, in a case of an adult, it is usually desirable to administer 0.001 to 100 mg, preferably 0.01 to 10 mg, and particularly preferably 0.1 to 0.4 mg as compound A per day in one to three parts.
  • nicotinic acid or a solvate thereof it is desirable to administer 0.01 to 800 mg, preferably 0.1 to 400 mg, and particularly preferably 1 to 100 mg as nicotinic acid per day in one to three parts.
  • a solvent 0.5% methylcellulose aqueous solution: MC
  • compound A alone nicotinic acid alone
  • combination of compound A and nicotinic acid was orally administered once per day.
  • Group 3 100 mg/kg of nicotinic acid
  • Group 4 0.1 mg/kg of compound A and 100 mg/kg of nicotinic acid
  • Results were presented by an average value ⁇ standard deviation. Comparison between the control group and each of the pharmaceutical agent administration groups was performed by a multiple comparison test of Dunnett, and a risk rate of less than 5% was determined to have a significant difference.
  • FIG. 1 illustrates results of measurement of LDL-C.
  • Compound A alone or nicotinic acid alone did not exhibit a clear effect on LDL-C, but combination use thereof exhibited a 26% lowering effect.
  • the combination use group exhibited a significant lowering effect compared not only with the Control group but also with the single pharmaceutical agent administration groups (Tukey's test). Therefore, it has been revealed that combined administration of the two compounds exhibits a strong effect of lowering lipid specifically on LDL-C.
  • the pharmaceutical composition and the medicine according to the present invention exhibit an excellent effect of lowering LDL-C in blood, are useful for preventing and/or treating dyslipidemia, particularly hyper LDL cholesterolemia, and therefore have industrial applicability.

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  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US15/513,609 2014-09-26 2015-09-28 Dyslipidemia therapeutic agent Abandoned US20170304274A1 (en)

Applications Claiming Priority (3)

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JP2014196002 2014-09-26
JP2014-196002 2014-09-26
PCT/JP2015/077235 WO2016047800A1 (ja) 2014-09-26 2015-09-28 脂質異常症治療剤

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US16/853,121 Abandoned US20200246314A1 (en) 2014-09-26 2020-04-20 Dyslipidemia therapeutic agent

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EP (1) EP3199153A4 (zh)
JP (1) JP6761347B2 (zh)
KR (1) KR20170058956A (zh)
CN (1) CN106714798B (zh)
TW (1) TW201618777A (zh)
WO (1) WO2016047800A1 (zh)

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EP3398601A1 (en) * 2017-05-02 2018-11-07 Salmon Pharma GmbH Nicotinamide for treating dyslipidemia
WO2020138406A1 (ja) * 2018-12-27 2020-07-02 興和株式会社 医薬組成物

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ZA200601272B (en) * 2003-09-03 2007-04-25 Kowa Co PPAR-activating compound and pharmaceutical composition containing same
EA009374B1 (ru) * 2003-09-03 2007-12-28 Кова Ко., Лтд. Активирующее ppar соединение и содержащая его фармацевтическая композиция
EP2114151A4 (en) * 2007-03-01 2010-03-17 Concourse Health Sciences Llc INOSITOL NIACINATE ISOMERS AND USES THEREOF

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TW201618777A (zh) 2016-06-01
CN106714798B (zh) 2020-11-06
KR20170058956A (ko) 2017-05-29
EP3199153A1 (en) 2017-08-02
WO2016047800A1 (ja) 2016-03-31
CN106714798A (zh) 2017-05-24
JPWO2016047800A1 (ja) 2017-07-06
EP3199153A4 (en) 2018-02-28
JP6761347B2 (ja) 2020-09-23

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